Publications
85 results found
Donnelly A, Yata T, Bentayebi K, et al., 2015, Bacteriophage mediates efficient gene transfer in combination with conventional transfection reagents, Viruses-Basel, Vol: 7, Pages: 6476-6489, ISSN: 1999-4915
The development of commercially available transfection reagents for gene transfer applications has revolutionized the field of molecular biology and scientific research. However, the challenge remains in ensuring that they are efficient, safe, reproducible and cost effective. Bacteriophage (phage)-based viral vectors have the potential to be utilized for general gene transfer applications within research and industry. Yet, they require adaptations in order to enable them to efficiently enter cells and overcome mammalian cellular barriers, as they infect bacteria only; furthermore, limited progress has been made at increasing their efficiency. The production of a novel hybrid nanocomplex system consisting of two different nanomaterial systems, phage vectors and conventional transfection reagents, could overcome these limitations. Here we demonstrate that the combination of cationic lipids, cationic polymers or calcium phosphate with M13 bacteriophage-derived vectors, engineered to carry a mammalian transgene cassette, resulted in increased cellular attachment, entry and improved transgene expression in human cells. Moreover, addition of a targeting ligand into the nanocomplex system, through genetic engineering of the phage capsid further increased gene expression and was effective in a stable cell line generation application. Overall, this new hybrid nanocomplex system i) provides enhanced phage-mediated gene transfer, ii) is applicable for laboratory transfection processes and iii) shows promise within industry for large-scale gene transfer applications.
Abaitua F, Przystal J, Hajitou A, et al., 2015, Arginine deprivation using ADI-PEG20 leads to regression of an ASS1-ve intracranial GBM tumor in mice and potentiates gamma irradiation of ASS1+ve GBM in vitro, 106th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Pasqualini R, Millikan RE, Christianson DR, et al., 2015, Targeting the interleukin-11 receptor alpha in metastatic prostate cancer: A first-in-man study, Cancer, Vol: 121, Pages: 2411-2421, ISSN: 0008-543X
BACKGROUNDReceptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors (“vascular zip codes”) within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature.METHODSThe authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα–based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer.RESULTSBMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m2). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine.CONCLUSIONSThese biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a large
Yata T, Lee ELQ, Suwan K, et al., 2015, Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors, Molecular Cancer, Vol: 14, ISSN: 1476-4598
Pranjol MZI, Hajitou A, 2015, Bacteriophage-Derived Vectors for Targeted Cancer Gene Therapy, VIRUSES-BASEL, Vol: 7, Pages: 268-284, ISSN: 1999-4915
Cancer gene therapy expanded and reached its pinnaclein research in the last decade. Both viral and non-viral vectors have entered clinical trials,and significant successes have beenachieved. However, a systemic administration of a vector,illustrating safe, efficient,and targeted gene delivery to solid tumors has proven to bea major challenge. In this review, we summarize the current progress and challenges in the targeted gene therapyof cancer. Moreover, we highlight the recent developments of bacteriophage-derived vectors and their contributions in targeting cancer with therapeutic genes following systemic administration.
Asavarut P, O'Neill K, Syed N, et al., 2014, Chimeric adeno-associated virus and bacteriophage: a potential targeted gene therapy vector for malignant glioma., Ther Deliv, Vol: 5, Pages: 975-990
The incipient development of gene therapy for cancer has fuelled its progression from bench to bedside in mere decades. Of all malignancies that exist, gliomas are the largest class of brain tumors, and are renowned for their aggressiveness and resistance to therapy. In order for gene therapy to achieve clinical success, a multitude of barriers ranging from glioma tumor physiology to vector biology must be overcome. Many viral gene delivery systems have been subjected to clinical investigation; however, with highly limited success. In this review, the current progress and challenges of gene therapy for malignant glioma are discussed. Moreover, we highlight the hybrid adeno-associated virus and bacteriophage vector as a potential candidate for targeted gene delivery to brain tumors.
Yata T, Lee K-Y, Dharakul T, et al., 2014, Hybrid Nanomaterial Complexes for Advanced Phage-guided Gene Delivery, MOLECULAR THERAPY-NUCLEIC ACIDS, Vol: 3, ISSN: 2162-2531
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- Citations: 30
Asavarut P, Hajitou A, 2014, The phage revolution against antibiotic resistance, The Lancet Infectious Diseases, Vol: 14, Pages: 686-686, ISSN: 1473-3099
Yata T, Nianiaris N, Songsivilai S, et al., 2014, Bacteriophage From Bacteria to a Successful Targeted Systemic Gene Delivery for Cancer, GENE THERAPY OF CANCER: TRANSLATIONAL APPROACHES FROM PRECLINICAL STUDIES TO CLINICAL IMPLEMENTATION, 3RD EDITION, Editors: Lattime, Gerson, Publisher: ELSEVIER ACADEMIC PRESS INC, Pages: 479-490, ISBN: 978-0-12-394295-1
Yata T, Lee K-Y, Stoneham CA, et al., 2013, Smart' bacteriophage nanocomplex: a hybrid multi-component particle for safe and efficient gene transfer, Collaborative Congress of the European-Society-for-Gene-and-Cell-Therapy and the Spanish-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A61-A61, ISSN: 1043-0342
Lee ELQ, Yata T, Hajitou A, 2013, Enhancing hybrid bacteriophage-mediated gene therapy for cancer treatment through extracellular matrix modulation, Collaborative Congress of the European-Society-for-Gene-and-Cell-Therapy and the Spanish-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A158-A159, ISSN: 1043-0342
Przystal JM, Pranjol Z, Nianiaris N, et al., 2013, Combination of temozolomide chemotherapeutic drug and promoter of the glucose-regulated protein 78 improves bacteriophage-mediated cancer gene therapy, Collaborative Congress of the European-Society-for-Gene-and-Cell-Therapy and the Spanish-Society-for-Gene-and-Cell-Therapy, Publisher: MARY ANN LIEBERT, INC, Pages: A158-A158, ISSN: 1043-0342
Kia A, Yata T, Hajji N, et al., 2013, Inhibition of histone deacetylation and DNA methylation improves gene expression mediated by the adeno-associated virus/phage in cancer cells, Viruses, Vol: 5, Pages: 2561-2572, ISSN: 1999-4915
Bacteriophage (phage), viruses that infect bacteria only, have become promising vectors for targeted systemic delivery of genes to cancer, although, with poor efficiency. We previously designed an improved phage vector by incorporating cis genetic elements of adeno-associated virus (AAV). This novel AAV/phage hybrid (AAVP) specifically targeted systemic delivery of therapeutic genes into tumors. To advance the AAVP vector, we recently introduced the stress-inducible Grp78 tumor specific promoter and found that this dual tumor-targeted AAVP provides persistent gene expression, over time, in cancer cells compared to silenced gene expression from the CMV promoter in the parental AAVP. Herein, we investigated the effect of histone deacetylation and DNA methylation on AAVP-mediated gene expression in cancer cells and explored the effect of cell confluence state on AAVP gene expression efficacy. Using a combination of AAVP expressing the GFP reporter gene, flow cytometry, inhibitors of histone deacetylation, and DNA methylation, we have demonstrated that histone deacetylation and DNA methylation are associated with silencing of gene expression from the CMV promoter in the parental AAVP. Importantly, inhibitors of histone deacetylases boost gene expression in cancer cells from the Grp78 promoter in the dual tumor-targeted AAVP. However, cell confluence had no effect on AAVP-guided gene expression. Our findings prove that combination of histone deacetylase inhibitor drugs with the Grp78 promoter is an effective approach to improve AAVP-mediated gene expression in cancer cells and should be considered for AAVP-based clinical cancer gene therapy.
Yata T, Lee K-Y, Stoneham C, et al., 2013, Novel bacteriophage-derived platform for advanced phage-guided gene transfer, Conference of the British-Society-for-Gene-and-Cell-Therapy (BSGCT), Publisher: MARY ANN LIEBERT INC, Pages: A19-A19, ISSN: 1043-0342
Przystal JM, Umukoro E, Stoneham CA, et al., 2013, Proteasome inhibition in cancer is associated with enhanced tumor targeting by the adeno-associated virus/phage, Molecular Oncology, Vol: 7, Pages: 55-66, ISSN: 1574-7891
Bacteriophage (phage), which are viruses that infect bacteria only, have shown promise as vehicles for targeted cancer gene therapy, albeit with poor efficiency. Recently, we generated an improved version of phage vectors by incorporating cis genetic elements of adeno‐associated virus (AAV). This novel AAV/phage hybrid (AAVP) efficiently delivered systemically administered therapeutic genes to various tumor targets by displaying an integrin tumor‐targeting ligand on the phage capsid. However, inherent limitations in bacteriophage mean that these AAVP vectors still need to be improved. One of the limitations of AAVP in mammalian cells may be its susceptibility to proteasomal degradation. The proteasome is upregulated in cancer and it is known that it constitutes a barrier to gene delivery by certain eukaryotic viruses. We report here that inhibition of proteasome improved targeted reporter gene delivery by AAVP in cancer cells in vitro and in tumors in vivo after intravenous vector administration to tumor‐bearing mice. We also show enhanced targeted tumor cell killing by AAVP upon proteasome inhibition. The AAVP particles persisted significantly in cancer cells in vitro and in tumors in vivo after systemic administration, and accumulated polyubiquitinated coat proteins. Our results suggest that the proteasome is indeed a barrier to tumor targeting by AAVP and indicate that a combination of proteasome‐inhibiting drugs and AAVP should be considered for clinical anticancer therapy.
Kia A, Przystal JM, Nianiaris N, et al., 2012, Dual Systemic Tumor Targeting with Ligand-Directed Phage and <i>Grp78</i> Promoter Induces Tumor Regression, MOLECULAR CANCER THERAPEUTICS, Vol: 11, Pages: 2566-2577, ISSN: 1535-7163
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- Citations: 33
Stoneham CA, Hollinshead M, Hajitou A, 2012, Clathrin-mediated Endocytosis and Subsequent Endo-Lysosomal Trafficking of Adeno-associated Virus/Phage, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 35849-35859
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- Citations: 45
Kia A, Przystal JM, Nianiaris N, et al., 2012, DUAL SYSTEMIC TUMOUR TARGETING WITH LIGAND-DIRECTED PHAGE AND <i>GRP78</i> PROMOTER INDUCES REGRESSION OF GLIOBLASTOMA, Conference of the British-Neuro-Oncology-Society (BNOS), Publisher: OXFORD UNIV PRESS INC, Pages: 5-5, ISSN: 1522-8517
Reebye V, Frilling A, Hajitou A, et al., 2012, A perspective on non-catalytic Src homology (SH) adaptor signalling proteins, CELLULAR SIGNALLING, Vol: 24, Pages: 388-392, ISSN: 0898-6568
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- Citations: 13
Stoneham C, Hajitou A, 2011, Investigation into the Entry and Intracellular Trafficking of a Bacteriophage-based Gene Therapy Vector, Publisher: MARY ANN LIEBERT INC, Pages: A108-A108, ISSN: 1043-0342
Reebye V, Bevan CL, Nohadani M, et al., 2010, Interaction between AR signalling and CRKL bypasses casodex inhibition in prostate cancer, CELLULAR SIGNALLING, Vol: 22, Pages: 1874-1881, ISSN: 0898-6568
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- Citations: 4
Hajitou A, 2010, Targeted Systemic Gene Therapy and Molecular Imaging of Cancer: Contribution of the Vascular-Targeted AAVP Vector, Adv Genet, Editors: Pasqualini, Pages: 65-82
Gene therapy and molecular-genetic imaging have faced a major problem: the lack of an efficient systemic gene delivery vector. Unquestionably, eukaryotic viruses have been the vectors of choice for gene delivery to mammalian cells; however, they have had limited success in systemic gene therapy. This is mainly due to undesired uptake by the liver and reticuloendothelial system, broad tropism for mammalian cells causing toxicity, and their immunogenicity. On the other hand, prokaryotic viruses such as bacteriophage (phage) have no tropism for mammalian cells, but can be engineered to deliver genes to these cells. However, phage-based vectors have inherently been considered poor vectors for mammalian cells. We have reported a new generation of vascular-targeted systemic hybrid prokaryotic-eukaryotic vectors as chimeras between an adeno-associated virus (AAV) and targeted bacteriophage (termed AAV/phage; AAVP). In this hybrid vector, the targeted bacteriophage serves as a shuttle to deliver the AAV transgene cassette inserted in an intergenomic region of the phage DNA genome. As a proof of concept, we assessed the in vivo efficacy of vector in animal models of cancer by displaying on the phage capsid the cyclic Arg-Gly-Asp (RGD-4C) ligand that binds to alphav integrin receptors specifically expressed on the angiogenic blood vessels of tumors. The ligand-directed vector was able to specifically deliver imaging and therapeutic transgenes to tumors in mice, rats, and dogs while sparing the normal organs. This chapter reviews some gene transfer strategies and the potential of the vascular-targeted AAVP vector for enhancing the effectiveness of existing systemic gene delivery and genetic-imaging technologies
Mitchell J, Paul P, Chen HJ, et al., 2010, Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase., PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCE (U S A), Vol: 107 (16), Pages: 7556-7561
We report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein. Similarly, lentiviral-mediated expression of R199W DAO in primary motor neuron cultures caused increased TUNEL labeling. This effect was also observed when motor neurons were cocultured on transduced astrocytes expressing R199W, indicating that the motor neuron cell death induced by this mutation is mediated by both cell autonomous and noncell autonomous processes. DAO controls the level of D-serine, which accumulates in the spinal cord in cases of sporadic ALS and in a mouse model of ALS, indicating that this abnormality may represent a fundamental component of ALS pathogenesis.
Hajitou A, 2010, A Hybrid Bacteriophage-Based Vector for Targeted Systemic Gene Delivery to Tumour Vasculature, 7th Annual Conference of the British-Society-for-Gene-Therapy, Publisher: MARY ANN LIEBERT INC, Pages: 491-492, ISSN: 1043-0342
Hajitou A, 2010, Targeted Systemic Gene Therapy and Molecular Imaging of Cancer: Contribution of the Vascular-Targeted AAVP Vector, TISSUE-SPECIFIC VASCULAR ENDOTHELIAL SIGNALS AND VECTOR TARGETING, PT B, Vol: 69, Pages: 65-82, ISSN: 0065-2660
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- Citations: 22
Trepel M, Stoneham CA, Eleftherohorinou H, et al., 2009, A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage-mediated, vascular-targeted suicide gene transfer, MOLECULAR CANCER THERAPEUTICS, Vol: 8, Pages: 2383-2391, ISSN: 1535-7163
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- Citations: 46
Trepel M, Stoneham CA, Mazarakis ND, et al., 2009, A Heterotypic Bystander Effect Observed for Tumor Cell Killing after AAVP-Mediated Vascular-Targeted Suicide Gene Transfer, 12th Annual Meeting of the American Society of Gene Therapy, Publisher: NATURE PUBLISHING GROUP, Pages: S108-S108, ISSN: 1525-0016
Paoloni MC, Tandle A, Mazcko C, et al., 2009, Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNF alpha to Cancer Vasculature, PLOS ONE, Vol: 4, ISSN: 1932-6203
Background:Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial ofthe Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturallydevelop in pet dogs into the development path of new human drugs. Trials are designed to address questions challengingin conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuableaddition to successful studies of cancer biology and novel therapeutic drug, imaging and device development.Methodology/Principal Findings:Through this established infrastructure, the first trial of the COTC (COTC001) evaluated atargeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF)toaV integrins on tumor endothelium. Trialprogress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for theconsortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (561012transducing unitsintravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normaltissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the definedoptimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), anddisease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST).Conclusions/Significance:The first study of the COTC has demonstrated the utility and efficiency of the establishedinfrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. Thepreclinical evaluation of RGD-A-TNFwithin this network provided valuable and necessary data to complete the design offirst-in-man studies.
De Belleroche JS, Mitchell J, Paul P, et al., 2009, A Novel Putative Familial ALS Locus on Chromosome 12: D-Amino Acid Oxidase, 61st Annual Meeting of American-Academy-of-Neurology, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: A114-A114, ISSN: 0028-3878
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- Citations: 1
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